Open AccessTranslesion polymerase eta both facilitates DNA replication and promotes increased human genetic variation at common fragile sites
Author(s) -
Shyam Twayana,
Albino Bacolla,
Angelica Barreto-Galvez,
Ruth B De-Paula,
William C. Drosopoulos,
Settapong T Kosiyatrakul,
Eric E. Bouhassira,
John A. Tainer,
Advaitha Madireddy,
Carl L. Schildkraut
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2106477118
Subject(s) - dna replication , biology , chromosomal fragile site , dna polymerase , genetics , processivity , genome instability , replication timing , dna polymerase ii , eukaryotic dna replication , control of chromosome duplication , microbiology and biotechnology , gene , dna , dna damage , chromosome , polymerase chain reaction , reverse transcriptase
Significance Common fragile sites (CFSs) are normal loci that are genetically unstable under normal and oncogenic replication stress. Pol eta has been proposed to play a key role in CFS replication. Here, we show that in the absence of Pol eta, replication at five specific CFS loci is perturbed, with fork pausing observed at several sites. Sequence analysis showed that certain pause sites are associated with the presence of non-B DNA motifs, while others are not. Importantly, pause sites are located within regions of increased genetic variation in healthy human populations that could be attributed to Pol eta activity. Our data unveil a role for Pol eta in overcoming replication stress, reducing DNA breakage, and promoting genetic variation at CFSs.